Cultures of skin fibroblasts, peripheral blood lymphocytes and lymphoblastoid cell lines from normal and cancer-prone individuals, as well as neoplastic cells transformed in culture or in vivo, were utilized in evaluating the relationship between radiation-induced chromosomal DNA damage, deficient DNA repair, genetic instability, cancer susceptibility and neoplastic transformation. The persistence of chromatid damage after x-irradiation just before mitosis is associated with both a predisposition to cancer and neoplastic transformation, and can provide the basis of a test for genetic susceptibility to cancer. Efforts are currently directed toward developing such an assay using skin fibroblasts, peripheral blood lymphocytes or lymphoblastoid cell lines. A genetic basis for this response to DNA damage with localization of genes to specific chromosomes is indicated from studies with somatic cell hybrids, inbred strains of mice, congenic mouse strains and chromosome transfers by microcell fusion; studies are in progress to localize and map such gene loci. The persistence of chromatid damage appears to result from deficient DNA repair during G2. Another aspect of this project is to follow in human epithelial cells the progression of biologic changes leading to neoplastic transformation, with particular emphasis on the acquisition of DNA repair deficiencies and genetic instability.